CTRP9 engages AdipoR1 and promotes T cell glycolysis and immunity

The adiponectin (ADPN) receptor (AdipoR) modulates T-cell responses, but its effects remain controversial. Given ADPN–AdipoR interaction inhibits T-cell responses and multiple AdipoR ligands exist, we hypothesize that ligand diversity underlies the differential regulation of AdipoR in T-cell immunity. To investigate this, we employed both tilapia and mouse models. Tilapia encodes AdipoR1 but lacks ADPN. Instead, an alternative adipokine, CTRP9, engages AdipoR1. CTRP9–AdipoR1 interaction triggers Ca2+ influx and activates CaM–CaMKKβ–AMPK pathway, thereby facilitating the crosstalk with TCR signaling. This cascade enhances T-cell activation, proliferation, and antimicrobial immunity by promoting glycolysis. Similarly, in mice, CTRP9 enhances T-cell activation, proliferation, and cytokine production. Moreover, CTRP9 improves the efficacy of anti-CD19 CAR-T cells in eliminating B-cell lymphoma in vitro. These findings reveal a previously unrecognized yet evolutionarily conserved role of CTRP9 in promoting T-cell immunity, in contrast to the inhibitory effect exerted by ADPN. Mechanistically, CTRP9 and ADPN exert distinct effects on T-cell metabolism; while CTRP9 enhances T-cell glycolysis, ADPN suppresses it. Thus, we propose AdipoR1 differentially regulates T-cell immune outcomes by selectively recognizing distinct adipokines: CTRP9 or ADPN.